Varicella zoster virus (VZV) is an important human pathogen that is restricted to growth in human tissues and cells. The primary goal of this project is to learn how VZV grows in human skin, and what effects it has on the intracellular environment of skin cells. Our hypothesis is that the molecular interaction of VZV with the host is fundamentally different in skin organ culture than in cultured cells. We will approach this issue by developing the skin organ culture (SOC) model of VZV replication, study the assembly of VZV in this skin model, and test the phenotype of VZV mutants. The SOC model will also allow us to study the effects of VZV infection on the host cells. Our second aim is to investigate the effects of VZV infection on signal transduction pathways in skin cells. We will measure the level of tyrosine phosphorylation, an early event in signal transduction, and then use a panel of antibodies to study the three major downstream pathways. Finally, chemical inhibitors of the signal transduction kinases will be used to determine their effect on VZV replication. Ultimately, the skin organ culture model may help us improve vaccine safety by identifying VZV virulence genes, and provide new ideas for antiviral drugs that target viral and cellular proteins.